Background
Nelarabine is a purine nucleoside analogue prodrug approved for the treatment of relapsed and refractory T‐cell acute lymphoblastic leukemia (R/R T‐ALL) and lymphoblastic lymphoma (T‐LBL). ...Although effective in R/R T‐ALL, significant neurotoxicity is dose‐limiting and such neurotoxicity associated with nucleoside analogues can be related to dosing schedule.
Methods
The authors conducted a phase 1 study to evaluate the pharmacokinetics and toxicity of nelarabine administered as a continuous infusion (CI) for 5 days (120 hours), rather than the standard, short‐infusion approach.
Results
Twenty‐nine patients with R/R T‐ALL/LBL or T‐cell prolymphocytic leukemia (T‐PLL) were treated, with escalating doses of nelarabine from 100 to 800 mg/m2/day × 5 days. The median age of the patients was 39 years (range, 14–77 years). The overall response rate was 31%, including 27% complete remission (CR) or CR with incomplete platelet recovery (CRp). Peripheral neuropathy was observed in 34% of patients, including four ≥grade 3 events related to nelarabine. Notably, there was no nelarabine‐related central neurotoxicity on study. The maximum tolerated dose was not reached. Pharmacokinetic data suggested no relationship between dose of nelarabine and accumulation of active intracellular ara‐GTP metabolite. Higher intracellular ara‐GTP concentrations were statistically associated with a favorable clinical response.
Conclusion
Preliminary evaluation of continuous infusion schedule of nelarabine suggests that the safety profile is acceptable for this patient population, with clinical activity observed even at low doses and could broaden the use of nelarabine both as single agent and in combinations by potentially mitigating the risk of central nervous system toxicities.
Nelarabine administered as continuous infusion is safe and has significant clinical activity in patients with T‐cell leukemia. The continuous infusion schedule of nelarabine was not associated with central neurotoxicity in this study.
Background
Acute myeloid leukemia (AML) with rearrangement of lysine methyltransferase 2a gene (KMT2Ar) is characterized by chemotherapy resistance and high rates of relapse. However, additional ...causes of treatment failure or early mortality have not been well‐defined in this entity.
Methods
In a retrospective analysis, causes and rates of early mortality following induction treatment were compared between a cohort of adults with KMT2Ar AML (N = 172) and an age‐matched cohort of patients with normal karyotype AML (N = 522).
Results
The 60‐day mortality in patients with KMT2Ar AML was 15% compared with 7% with normal karyotype (p = .04). We found a significantly higher occurrence of major bleeding events (p = .005) and total bleeding events (p = .001) in KMT2Ar AML compared with diploid AML. Among evaluable patients with KMT2Ar AML, 93% exhibited overt disseminated intravascular coagulopathy compared with 54% of patients with a normal karyotype before death (p = .03). In a multivariate analysis, KMT2Ar and a monocytic phenotypic were the only independent predictors of any bleeding event in patients who died within 60 days (odds ratio, 3.5; 95% CI, 1.4–10.4; p = .03; odds ratio, 3.2; 95% CI, 1–1‐9.4; p = .04, respectively).
Conclusion
In conclusion, early recognition and aggressive management of disseminated intravascular coagulopathy and coagulopathy are important considerations that could mitigate the risk of death during induction treatment in KMT2Ar AML.
Plain Language Summary
Acute myeloid leukemia (AML) with rearrangement of KMT2A is characterized by chemotherapy resistance and high rates of relapse. However, additional causes of treatment failure or early mortality have not been well‐defined in this entity.
In this article, that KMT2A‐rearranged AML is demonstrably associated with higher early mortality and an increased risk of bleeding and coagulopathy, specifically, disseminated intravascular coagulation, compared with normal karyotype AML.
These findings emphasize the importance of monitoring and mitigating coagulopathy in KMT2A‐rearranged leukemia similar to what is done in acute promyelocytic leukemia.
KMT2Ar acute myeloid leukemia (AML) is associated with increased major and minor bleeding events, disseminated intravascular coagulopathy (DIC), and early mortality. Early recognition and aggressive management of DIC and coagulopathy could mitigate the risk of death during induction therapy in KMT2Ar AML.
Background
Immune checkpoint inhibitors (ICI), combined with hypomethylating agents, can be used to treat acute myeloid leukemia (AML), but this strategy results in a high rate of pneumonitis. The ...authors sought to determine risk factors for pneumonitis development and whether pneumonitis increased mortality.
Methods
The authors conducted a retrospective review of 258 AML patients who received ICI‐containing regimens from 2016 to 2018. A multidisciplinary adjudication committee diagnosed pneumonia and pneumonitis by reviewing symptoms, imaging, microbiology, and response to therapies. To measure risk factors for pneumonitis and mortality, multivariate Cox proportional hazards models were constructed. Pneumonia, pneumonitis, and disease progression were modeled as a time‐dependent variable and incorporated a standard risk set modifying variables into the models.
Results
Thirty patients developed pneumonitis (12%). Of these, 17 had partial or complete resolution, whereas 13 patients died from pneumonitis. Increasing age (hazard ratio HR, 1.04 per year; 95% confidence interval CI, 1.00‐1.08), and baseline shortness of breath increased pneumonitis risk (HR, 2.51; 95% CI, 1.13‐5.55). Female sex (HR, 0.33; 95% CI, 0.15‐0.70) and increasing platelet count (HR, 0.52 per log‐unit increase; 95% CI, 0.30‐0.92) decreased pneumonitis risk. In adjusted models, ICI‐related pneumonitis significantly increased mortality (HR, 2.84; 95% CI, 1.84‐4.37).
Conclusions
ICI‐related pneumonitis occurs at a high rate in AML patients and increases mortality.
Lay Summary
Immune checkpoint inhibitors (ICIs) remove inhibitory signals that reduce T‐cell function and allow T‐cells to better attack cancer cells.
In acute myeloid leukemia (AML), the effectiveness of ICIs is limited in part by inflammation of the lung, called pneumonitis.
This study reviewed 258 patients with AML who received ICIs and identified 30 patients who developed pneumonitis, nearly half of whom died.
Older age and baseline shortness of breath increased pneumonitis risk, whereas female sex and higher baseline platelet counts decreased pneumonitis risk.
Pneumonitis increased mortality by nearly 3‐fold.
This work highlights the significant harm imposed by pneumonitis after ICI therapies.
Pneumonitis occurs in 12% of patients with acute myeloid leukemia undergoing immune checkpoint inhibitor therapy and increases mortality by nearly 3‐fold.
Background
Nilotinib is a potent, second‐generation inhibitor of BCR‐ABL1 tyrosine kinase and has been approved as frontline and salvage therapy for patients with chronic‐phase chronic myeloid ...leukemia (CP‐CML).
Methods
In this single‐institution, phase 2 study, 122 patients with newly diagnosed CP‐CML received nilotinib 400 mg twice daily. The median follow‐up on study was 78.3 months (interquartile range, 58.4‐96.5 months).
Results
Fifty‐six percent of patients remained on therapy at the last follow‐up. Both the complete cytogenetic response rate and the major molecular response (MR) rate were 91%. Seventy‐five percent and 59% of patients achieved a ≥4.5‐log reduction in BCR‐ABL1 transcripts (MR4.5) and a sustained MR4.5 beyond 2 years, respectively. The estimated event‐free survival and overall survival rates at 5 years were 89% and 93%, respectively, and the corresponding rates at 10 years were 85% and 88%, respectively. Treatment discontinuation due to toxicity occurred in 19% of patients, mostly because of cardiovascular events (10%) and biochemical abnormalities (6%). The top 3 nonhematologic toxicities were rash (55%), elevated bilirubin (57%), and elevated aminotransferases (48%). Hematologic toxicity was transient and mild. Ischemic cardiovascular adverse events occurred in 8% of patients. Four patients (3%) progressed to accelerated or blast phase while on therapy, and 7 patients (6%) died on study.
Conclusions
The current data confirm the long‐term efficacy of nilotinib 400 mg twice daily in patients with CP‐CML. A majority of patients can achieve sustained MR4.5.
Nilotinib is effective frontline treatment for patients with early chronic‐phase chronic myeloid leukemia, resulting in a high rate of deep and sustained molecular responses. The long‐term safety profile remains favorable.
Liposomal vincristine is designed to reduce neurotoxicity and increase dose intensity delivery, and has been approved as salvage therapy in relapsed/refractory acute lymphoblastic leukemia (ALL). Our ...aim was to evaluate the response rate, toxicities, and outcome of adults with newly diagnosed ALL who received liposomal vincristine, rather than regular vincristine in combination with intensive chemotherapy (Hyper‐CMAD). In a single‐center, phase 2 study, patients ≥18 years with newly‐diagnosed B‐cell ALL were eligible to receive hyper‐CMAD alternating with high‐dose methotrexate and cytarabine. Rituximab was administered in CD20 positive ALL. Tyrosine kinase inhibitors (imatinib or dasatinib) were added in Philadelphia chromosome‐positive (Ph‐positive) ALL. Thirty‐one patients were enrolled, median follow‐up of 59 months (0.3‐70). Thirteen patients (42%) had CD20 positive ALL, and 21 (68%) had Ph‐positive ALL. Thirty (97%) achieved complete remission (CR). All 26 patients with abnormal karyotype achieved complete cytogenetic response (CCyR), and 27/30 (90%) achieved negative minimal residual disease status by multicolor flow cytometry. Of 20 evaluable Ph‐positive ALL patients, major molecular response (MMR) was achieved in 19 patients (95%); complete molecular response (CMR) in 14 (70%). Grade 3/4 peripheral neuropathy was observed in five (16%) with all grade peripheral neuropathy in 21 (68%). With a median follow‐up of 59 months, 21 (68%) patients are alive. The 5‐year CR duration and survival rates were 73% and 61%, respectively. Ten (32%) patients died: one, sepsis on C1D10; four, unknown; one, post‐transplant complications; four, relapse. Hyper‐CMAD with liposomal vincristine is safe and demonstrated high response and survival rates in newly diagnosed ALL.
Various trials have reported improved outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) who received treatment with pediatric-based regimens. Those reports ...prompted the current investigation of the pediatric augmented Berlin-Frankfurt-Münster (ABFM) regimen in AYA patients. The results were compared with those from a similar population that received the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen.
Eighty-five patients ages 12 to 40 years who had Philadelphia chromosome (Ph)-negative ALL received the ABFM regimen from October 2006 through April 2012. Their outcome was compared with outcomes in 71 historic AYA patients who received hyper-CVAD from the authors' institution. Patient and disease characteristics, as well as minimal residual disease status, were analyzed for their impact on outcomes.
The complete response rate with ABFM was 94%. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 70% and 74%, respectively. For patients aged ≤21 years, the 3-year CRD and OS rates were 72% and 85%, respectively; and, for patients ages 21 to 40 years, the respective rates were 69% and 60%. The initial white blood cell count was an independent predictive factor of OS and CRD. The minimal residual disease status on days 29 and 84 of therapy also were predictive of long-term outcomes. Severe regimen toxicities included transient hepatotoxicity in 35% to 39% of patients, pancreatitis in 11% of patients, osteonecrosis in 11% of patients, and thrombosis in 22% of patients. The 3-year OS rate was 74% in the ABFM group versus 71% in the hyper-CVAD group, and the corresponding 3-year CRD rate was 70% versus 66%, respectively.
ABFM was tolerable in AYA patients with ALL but was not associated with significant improvements in CRD and OS compared with hyper-CVAD.
Response rates in chronic myeloid leukemia (CML) are now reported based on the cumulative incidence of a single-time best response. The study aim was to examine the significance of different response ...criteria for CML on imatinib therapy.
In all, 276 patients with chronic phase CML on imatinib therapy were analyzed. Cytogenetic and molecular responses were coded as to single best response and response at specific intervals of treatment.
The cumulative incidence of complete cytogenetic response (CGCR) with imatinib was 91%; however, the incidence of CGCR at 48 months into therapy was only 78%. Similarly, the incidence of major molecular responses (best cumulative vs landmark at 48 months) were 74% versus 62%, and of undetectable BCR-ABL transcripts 38% versus 24%. There was a strong association between achievement of major cytogenetic response (Philadelphia chromosome Ph-positivity <or=35%) at 6 months to 12 months and survival as well as progression-free survival (PFS). Achievement of major molecular response (vs lesser molecular response) in patients in complete cytogenetic response was not associated with significant differences in survival, but showed some association with PFS. Durable CGCR and major molecular responses (documented continuously for >or=12 months) were associated with longer PFS duration but not with survival duration differences. Of interest, major molecular responses documented at least twice were noted in 71% of patients on imatinib therapy; undetectable BCR-ABL transcripts documented at least twice were noted in 34%.
Achievement and durability of CGCR and of major and complete molecular responses at landmark times predict outcome in CML, and may help in comparing the efficacy of different treatments.
Recently, the discovery of biological and clinical properties of mutated isoforms 1 and 2 mutations of isocitrate dehydrogenases (IDH) 1 and 2, affecting approximately 20% of patients with acute ...myeloid leukemia (AML), lead to the development of an individualized treatment strategy. Promoting differentiation and maturation of the malignant clone targeting IDH is an emerging strategy to promote clinical responses in AML. Phase I/II trials have shown evidence of safety, tolerability, and encouraging evidence of efficacy of two small molecule inhibitors targeting IDH2 and IDH1 gene mutations, respectively enasidenib and ivosidenib. In this review, the contribution of IDH1/IDH2 mutations in leukemogenesis and progress of targeted therapeutics in AML will be highlighted.
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